Hallmarks of Aging in the Liver

Abstract

While the liver demonstrates remarkable resilience during aging, there is growing evidence that it undergoes all the cellular hallmarks of aging, which increases the risk of liver and systemic disease. The aging process in the liver is driven by alterations of the genome and epigenome that contribute to dysregulation of mitochondrial function and nutrient sensing pathways, leading to cellular senescence and low-grade inflammation. These changes promote multiple phenotypic changes in all liver cells (hepatocytes, liver sinusoidal endothelial, hepatic stellate and Küpffer cells) and impairment of hepatic function. In particular, age-related changes in the liver sinusoidal endothelial cells are a significant but under-recognized risk factor for the development of age-related cardiometabolic disease.

Keywords: AMPK, 5′ adenosine monophosphate-activated protein kinase; CR, caloric restriction; Endothelial; FOXO, forkhead box O; Genetic; HSC, hepatic stellate cell; Hepatocyte; IGF-1, insulin like growth factor 1; IL-6, interleukin 6; IL-8, interleukin 8; KC, Küpffer cell; LSEC, liver sinusoidal endothelial cell; Mitochondrial dysfunction; NAD, nicotinamide adenine dinucleotide; NAFLD, non-alcoholic fatty liver disease; NO, nitric oxide; Nutrient sensing pathways; PDGF, platelet derived growth factor; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-α; ROS, reactive oxygen species; SIRT1, sirtuin 1; Senescence; TNFα, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; mTOR, mammalian target of rapamycin; miR, microRNA; αSMA, alpha smooth muscle actin.

Graphical abstract

Fig. 1

The aging liver. In the young liver solutes such as lipoproteins, insulin and carbohydrates are able to diffuse between the blood and hepatocytes, via the LSECs fenestrations. Intercellular communication via the release of vascular endothelial growth factor (VEGF) from hepatocytes and nitric oxide (NO) and hepatocyte growth factor (HGF) from LSECs and HSCs maintain the homeostatic phenotype of these liver cells. With age there are multiple changes to each cell type impairing the VEGF, NO and HGF dynamic. Hepatocytes demonstrate increased polyploidy and DNA damage, accumulation of lipofuscin, reduced mitochondrial oxidative capacity, increased oxidative stress and reactive oxygen species (ROS) and senescent cell accumulation with senescence associated secretory phenotype (SASP) (Section 2). SASP promotes recruitment of inflammatory cells. LSECs have reduced fenestrations, impaired angiocrine factor release and cellular autophagy as well as increased cell adhesion marker expression (Section 3). HSCs demonstrate phenotypical changes such as increased lipid loading, collagen and lamina production leading to basal membrane (BM) deposition, impaired vitamin A metabolism, promoting low-grade inflammation (Section 4). KCs accumulate within the liver with age and adhere to the adhesion markers expressed on LSECs. KCs contribute to the low-grade inflammation of the liver and drive interleukin 6 (IL-6) release but demonstrate impaired phagocytosis (Section 5). Abbreviations: a: activated; dx: dysfunction; q: quiescent.

Fig. 2

Summary of changes that occur in the liver sinusoidal endothelial cell with aging. (a) loss of fenestrations and (b) pathways promoting ROS and cellular senescence in aging LSECs. Abbreviations: AMPK: 5′ adenosine monophosphate-activated protein kinase; BM: bone marrow; cGMP: cyclic guanosine monophosphate; EPC: endothelial progenitor cell; HGF: hepatocyte growth factor; ICAM-1: intercellular adhesion molecule 1; Id1: inhibitor of differentiation/DNA binding protein 1; IL-6: interleukin 6; NAD: nicotinamide adenine dinucleotide; NO: nitric oxide; ROS: reactive oxygen species; SIRT1: sirtuin 1; VEGF: vascular endothelial growth factor; WF: von Willebrand factor.

Fig. 3

Holistic model for integrating the hallmarks of aging within the liver. Interconnectome based on computational modeling of aging by Mc Auley and Mooney [151], Mc Auley and Mooney [152] and the data presented in this review. Green: nucleus related, red: external factors; Blue: metabolic related; Purple: mitochondrial related. Genomic stability is a key regulator of aging (Section 6.1) with methylation status (Section 6.3), genetic mutation (Section 6.3) and external stressors. Regulation of the transcription networks in both the nucleus and mitochondria occur by nutrient sensing pathways (Section 6.3) which are impaired with age (Section 6.6). Mitochondrial dysfunction (Section 6.7) leads to a shift in the balance of autophagy and oxidative stress in favor of stress contributing to the loss of proteostasis (Section 6.4) and impaired ER stress pathways (Section 6.5). In combination with telomere shortening (Section 6.2) there is a promotion of cellular senescence (Section 6.8). Abbreviations: AMPK: 5′ adenosine monophosphate-activated protein kinase; ISS: insulin/insulin like growth factor 1 signaling; mTOR: mammalian target of rapamycin; PARP: protein poly(ADP-ribose) polymerase; SIRT: sirtuin.